DK160826B - 4-(imidazolyl eller triazolyl)methyl-1,3-dioxolan eller -thioxo-1,3-dioxolanderivater og antimykotiske praeparater indeholdende disse - Google Patents
4-(imidazolyl eller triazolyl)methyl-1,3-dioxolan eller -thioxo-1,3-dioxolanderivater og antimykotiske praeparater indeholdende disse Download PDFInfo
- Publication number
- DK160826B DK160826B DK354684A DK354684A DK160826B DK 160826 B DK160826 B DK 160826B DK 354684 A DK354684 A DK 354684A DK 354684 A DK354684 A DK 354684A DK 160826 B DK160826 B DK 160826B
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- triazolyl
- azole
- alkyl
- halogen
- Prior art date
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- HTWIZMNMTWYQRN-UHFFFAOYSA-N 2-methyl-1,3-dioxolane Chemical compound CC1OCCO1 HTWIZMNMTWYQRN-UHFFFAOYSA-N 0.000 title claims description 6
- -1 IMIDAZOLYL Chemical class 0.000 title description 5
- 230000001857 anti-mycotic effect Effects 0.000 title description 5
- 239000002543 antimycotic Substances 0.000 title description 3
- 238000002360 preparation method Methods 0.000 title description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 claims description 6
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- KDQSFIADLVJROL-UHFFFAOYSA-N 1,3-dioxolane;1h-pyrrole Chemical class C1COCO1.C=1C=CNC=1 KDQSFIADLVJROL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 3
- 150000007980 azole derivatives Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- WGHMWTYSXYBZSU-UHFFFAOYSA-N 2-methyl-1,3-dioxole Chemical compound CC1OC=CO1 WGHMWTYSXYBZSU-UHFFFAOYSA-N 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000003429 antifungal agent Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- UALIIGYAUNFWEZ-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-(1,2,4-triazol-1-yl)propane-1,2-diol Chemical compound C1=NC=NN1CC(O)(C=1C(=CC(Cl)=CC=1)Cl)C(O)C1=CC=C(F)C=C1 UALIIGYAUNFWEZ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940095731 candida albicans Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical class C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- PFCHFHIRKBAQGU-UHFFFAOYSA-N 3-hexanone Chemical compound CCCC(=O)CC PFCHFHIRKBAQGU-UHFFFAOYSA-N 0.000 description 2
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000223238 Trichophyton Species 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- NALREUIWICQLPS-UHFFFAOYSA-N 7-imino-n,n-dimethylphenothiazin-3-amine;hydrochloride Chemical compound [Cl-].C1=C(N)C=C2SC3=CC(=[N+](C)C)C=CC3=NC2=C1 NALREUIWICQLPS-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000027700 hepatic dysfunction Diseases 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940032007 methylethyl ketone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
i
DK 160826 B
Den foreliggende opfindelse angår hidtil ukendte 4-(imidazolyl eller triazolyl)methyl-l,3-dioxolan- eller -thioxo-l,3-dioxolanderivater og antimykotiske præparater indeholdende disse. Opfindelsen angår forbindelser med formlen 5 cky^o R—C— C—CH— Az 10 hvori
Az er imidazolyl eller triazolyl, R er Ci-Cg-alkyl eller phenyl eventuelt substitueret med 1 til 3 substituenter udvalgt blandt halogen, Cj-Cg-alkyl og C1-C5-alkoxy, 15 hver af X1 og X2 er hydrogen, halogen, (^-Cg-alkyl, eller
Ci-Cg-alkoxy, Y er C=0 eller C=S, og farmaceutisk acceptable syreadditionssalte deraf, som er nyttige som antimykotiske midler.
20 Betydningerne af udtrykkene, som anvendes i ovennævnte definitioner forklares nedenfor: C^Cg-alkyl omfatter for eksempel methyl, ethyl, propyl, isopropyl, butyl, t-butyl og pentyl,
Ci-Cg-alkoxy omfatter methoxy, ethoxy, propoxy, isopropoxy, 25 butoxy, isobutoxy og pentyloxy, halogen omfatter fluor, chi or, brom og iod, og triazolyl omfatter lH-l,2,4-triazol-l-yl og 4H-l,2,4-triazol-4-yl. Ketokonazol (US-patentskrifterne nr. 4.144.346 og 4.223.036) anvendes allerede som et oralt antimykotisk middel i Europa og U.S.A., selv 30 om nogle uheldige virkninger deraf, såsom hepatisk dysfunktion, er blevet rapporteret. Der kendes også andre azol-dioxolan-derivater, benyttet som landbrugsfungicider samt som antimykotiske midler mod svampeinfektioner hos mennesker, fra GB-patentskrift nr. 2.095.236, men forsøgsdata på dyr er ikke beskrevet deri. Endvidere beskrives ingen dioxolan-deri- 35 vater indeholdende carbonyl, thiocarbonyl eller thioxo (=Y) i dioxolan-ringen i GB patentskrift 2.095.236. Det har nu vist sig, at de hidtil ukendte azol-derivater med formel (I) udviser kraftig antimykotisk aktivitet, når de administreres oralt.
DK 160826 B a
Forbindelserne med formel (I) ifølge opfindelsen kan fremstilles som angivet i følgende reaktionsskema:
OH OH
5 R-c—c—CH -Az Y-introducerende i I 2 middel Q3 “i—> (II) 0-^0 R-A-C— CH_-Az 10 a i hvori Az, R, X1, X2 og Y alle er som ovenfor defineret.
15 Forbindelserne med formel (I) ifølge opfindelsen kan fremstilles ved, at man omsætter udgangsmaterialet (II) med et Y-introducerende middel. Eksempler på Y-introducerende midler er imidazoler såsom Ι,Γ-carbonyldiimidazol eller Ι,Γ-thiocarbonyldiimidazol, phosgener såsom phosgen og thiophosgen, oxalylchlorid, dihalogenmethaner såsom brom-20 chlormethan og dibrommethan, halogencarbonsyreestre såsom ethylchlor-carbonat og phenylchlorcarbonat, og ketoner såsom acetone, methyl -ethyl keton, diethyl keton, ethyl propyl keton, dipropyl keton, cyclopent-anon, cyclohexanon og cycloheptanon.
Da forbindelserne med formel (I) indeholder asymmetriske carbon-25 atomer, fremstilles de almindeligvis som en blanding af diastereomere, som kan adskilles i de enkelte diastereomere på konventionelle måder.
Udgangsforbindelserne med formel (II) kan for eksempel fremstilles ifølge følgende reaktionssekvens: .—. Y1 Oxidation med 30 r_co-CH—^ seleniumdioxid ^ R-CO-CO—2 (m) (iv) 0 Indførelse 35 Oxiran- / \ f tHazol dannelse v R-C O-C-CH_ _v -—-} I 2 7* oti (V)
DK 160826 B
3
0H N OH OH N
R-Co|cH2Q Reduktion • ^ (vi) (ii) (GB-patentansøgning nr. 8.404.426) 10 hvori R, X1 og X2 er som ovenfor defineret.
Foretrukne forbindelser med formel (I) ifølge opfindelsen er sådanne med formlen 1R 0-"Ύ>0 ΛΤ
lo I I
R-C-C-CH -N
H ! * N=.
i ^* ^1 (Γ) 20 hvori R' er C3-C4-alkyl eller phenyl substitueret med 1 eller 2 halogenatomer, mindst den ene af X1' og X2' er halogen, og Y er C*=0 eller C=S.
Forbindelserne med formel (I) ifølge opfindelsen, der tilvejebrin- 25 ges som ovenfor anført, kan omdannes til farmaceutisk acceptable syreadditionssalte deraf. Eksempler på syrer, som kan danne disse salte er organiske syrer, såsom eddike-, citron-, vin-, æble-, rav-, malein-, fumar- og methansulfonsyre, og uorganiske syrer, såsom hydrogenhalogen-syrer, svovlsyre og phosphorsyre.
30 Forbindelserne med formel (I) ifølge opfindelsen og farmaceutisk acceptable salte deraf udviser kraftig antimykotisk aktivitet og er nyttige som antimykotiske midler til medicinsk eller veterinær brug. Forbindelserne med formel (I) er især nyttige som orale eller injiærbare antimykotiske midler.
35 Forbindelserne med formel (I) ifølge opfindelsen eller farmaceutisk acceptable syreadditionssalte deraf kan anvendes alene eller sammen med additiver, såsom bærere, excipienser, diluenter, dispergeringsmidler og lignende, i dosisformer til invortes og udvortes brug. Disse dosisformer
DK 160826 B
4 lignende, i dosisformer til i nvortes og udvortes brug. Disse dosisformer omfatter opløsninger, suspensioner, pulvere, piller, granulater, kapsler, tabletter, injektioner, salver, tinkturer, suppositorier og lignende, og disse præparater kan fremstilles på konventionelle måder for for-5 mulering. Forbindelserne med formel (I) kan administreres oralt til voksne i en dosis eller doser på 10 til 2000 mg pr. dag.
Desuden er forbindelserne med formel (I) ifølge opfindelsen eller de farmaceutisk acceptable syreadditionssalte deraf også nyttige som landbrugsfungicider7 når de anvendes landbrugsmæssigt på afgrøder, såsom 10 frugttræer, ris, hvede, bomuld, majs, sojabønner og lignende.
Opfindelsen belyses nærmere i de følgende eksempler.
Eksempel 1
OH OH N
15 i i 20 „ 25 ^1
En blanding af 500 mg 2-(2,4-dichlorphenyl)-l-(4-fluorphenyl)-3-(lH- l,2,4-triazol-l-yl)-l,2-propandiol, 530 mg Ι,Γ-carbonyldi imidazol og 10 ml tør chloroform opvarmes til tilbagesvaling i 1 time. Vand sættes til reaktionsblandingen og chloroformlaget skilles fra, tørres over vandig 30 natriumsulfat og koncentreres. Remanensen kromatograferes på en silica-gelkolonne, som elueres med en blanding af methylenchlorid og methanol (100:0 - 98:2 vol/vol). Eluatet koncentreres, og remanensen krystalliseres fra ethylacetat/isopropylether, hvilket giver 420 mg 4-(2,4-dichlorphenyl)-5-(4-fluorphenyl)-2-OXO-4-(1H-1,2,4-triazol-lyl)methyl-35 1,3-dioxolan som krystaller, smeltepunkt 191 til 192°C. Udbytte: 78,7%. Analyse. Beregnet for C18H12N303C12F (%): C, 52,96; H, 2,96; N, 10,29; Cl, 17,37; F, 4,65.
Fundet (%): C, 53,35; H, 3,15; tt, 10,42; Cl, 17,34; F, 4,84.
DK 160826 B
5
Nujol , IR v : 1810 cm'1 (C=0). max NMR (CDC13) S: 4,08 (d, J = 15Hz, IH) og 4,93 (d, J = 15Hz, IH) -CH2-; 6,08 (s, IH, -0-CH ); 7,03 til 7,90 (m, 9H, arom-H).
5
Eksempel 2 til 15
De følgende udgangsforbindelser med formel (ΙΓ) (forbindelser med formlen II, hvori Az er lH-l,2,4-triazol-l-yl) omsættes med Ι,Γ-carbonyldiimidazol på samme måde som i eksempel 1, hvilket giver de 10 tilsvarende forbindelser med formel (la) (forbindelser med formlen I, hvori Az er lH-l,2,4-triazol-l-yl og Y er C = 0) ifølge opfindelsen.
OK OH « I
R-C— C —CH Ji I 9^7
15 i I ^—* r-c—é—ch2/ ^I
Gi *1, M-x2 20 (II') (la)
Eks.
nr. R X1 X2 smp. (eC) Udbytte (%) 25 2 i-Pr 2C1 4C1 150-150,5 52,3 3 Ph 2C1 4C1 138-139 34,3 4 Bu 2C1 4C1 137-138 42,3 30 Cl 5 CI"C=^· 4C1 H 162-163 78,2 .Cl
35 rK
6 C1\J/ 2C1 4_C1 222-223 64,4
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6
Eks.
nr. R X1 X2 snip. (°C) Udbytte (%) 5 7 C=5" 2C1 H 234-235 93,4 8 4F H 81’82 69,4 9 Cl-O- 4C1 H 155-156 70,1 10 Cl 10 3C1 Η 148,5-149,5 57,9 11 CH3 -^y~ 4ch3 h 139-140 79,6 15 12 Pr 2C1 4C1 179-180 70,1 13 Pr 4C1 H 121-122 69,0 14 Ph 2C1 H 220-222 20,4 20 15 CH3-0- 2C1 H 195-196 26,0
Note: Forkortelserne i tabellen har følgende betydning.
Ph (phenyl), Pr (n-propyl), i-Pr (isopropyl), Bu (n-butyl).
25 O
Eksempel 16 0H 0H <1 so ^ ih; k=1 35 "C1 -> ^
Til en opløsning af 400 mg 2-(2,4-dichlorphenyl)-l-(4-fluorphenyl)- 3-(lH-l,2,4-triazol-l-yl)-l,2-propandiol og 430 mg triethylamin i 20 ml tør chloroform sættes en opløsning af 532 mg oxalylchlorid i 2 ml tør chloroform i små portioner under isafkøling, og blandingen omrøres ved 40 stuetemperatur i I time. Reaktionsbladingen blandes med is/vand og vandig natriumbicarbonatopløsning og ekstraheres med methylenchlorid.
Det organiske lag vaskes med vand, tørres over vandfri natriumsulfat og
DK 160826 B
7 koncentreres. Remanensen kromatograferes på en sil icagelkolonne, som elueres med benzen/ethylacetat (1:1 vol/vol). Eluatet koncentreres, og den resulterende remanens krystalliseres fra ethylacetat/isopropylether, hvilket giver 219 mg 4-(2,4-dichlorphenyl)-5-(4-fluorphenyl)-2-oxo-4-5 (lH-l,2,4-triazol-1-yl)methyl-1,3-dioxolan som krystaller, smeltepunkt 190 til 191“C. Udbytte: 51,3%.
Eksempel 17 til 21
De følgende udgangsforbindelser med formel (II) omsættes med oxa-10 lylchlorid på samme måde som i eksempel 16, hvilket giver de tilsvarende forbindelser med formel (Ib) (forbindelser med formel I, hvori Y er C =
f ?H oX
R—C— C—CH —Az „ 1 I
i i 2 R-C— C—CH„ -Az
‘Γχ1 _ II
w - Cfe (XI) (Ib) 20
Eks".
nr. R X1 X2 Az smp. (°C) Udbytte (%)
__ ~~cT
25 17 Cl-f> Η H Tr 145-146 64 18 F“C3“ 2C1 4C1 Im 209-212 77 30 19 4C1 H Tr 176-177 83 20 C./> 2C1 4C1 Im 238-239 51 35 21 Ph 2C1 4C1 Im 230-232 82
Note 1): Forkortelserne i tabellen har følgende betydning:
Im (lH-l,4-imidazol-lyl), Tr (lH-l,2,4-triazol-l-yl).
Eksempel 22
DK 160826 B
8
OH OH N
s --,
v X
10 C1 —9-
H ryC1N
15 C1
En opløsning af 500 mg 2-(2,4-dichlorphenyl)-l-(4-f|uorphenyl)-3- (lH-l,2,4-triazol-l-yl)-l,2-propandiol og 700 mg M'-thiocarbonyl- diimidazol i 10 ml tør chloroform opvarmes til tilbagesvaling i 1 time.
Til reaktionsblandingen sættes is/vand, og blandingen ekstraheres med 20 chloroform. Chloroformlaget vaskes med vand, tørres over vandfri natriumsulfat og koncentreres. Remanensen kromatograferes på en si licage!kolonne, som elueres med benzen/ethylacetat (4:1 vol/vol).
Eluaterne, som indeholder forbindelsen ifølge opfindelsen, samles og koncentreres. Remanensen vaskes med isopropyl ether, hvilket giver 25 krystallinske materialer. Krystallerne omkrystalli seres fra ethylacetat/isopropylether, hvilket giver 360 mg 4-(2,4-dichlorphenyl)- 5-(4-fluorphenyl)-2-thioxo-4-(lH-l,2,4-triazol-l-yl)methyl-l,3-dioxolan, smeltepunkt 169 til 170eC. Udbytte: 64,9%.
Analyse. Beregnet for C18H12N302C12FS (%): C, 50,96; 30 H, 2,85; N, 9,90; Cl, 16,71; F, 4,48; S, 7,56.
Fundet (%): C, 50,91; H, 2,98; N, 9,97; Cl, 16,51; F, 4,77; S, 7,69. IRj/Nujol. 13Q3^ 12go cm-l ^c=s^ max NMR (CDC1a) δ: 4,20 (d, 0 = 16,5Hz, IH) og 4,97 (d, J = 16,5Hz, 35 IH) -eng; 6,28 (s, IH), -0-CH-; 7,59 (s, IH) og 7,98 (s, IH) triazol H; 7,15 tiT 7,60 (m, 7H, arom-H).
Forsøg 1
Antimykotisk test overfor Trichophytonasteroides 40 Den minimale inhibitoriske koncentration (MIC, øg/ml) for hver testforbindelse overfor Trichophyton asteroides ved in vitro antimykolo-gisk test vises nedenfor. MIC bestemmes som beskrevet af T. Totani et
DK 160826 B
9 al, J. Med. Chem., 24 (12), 1492-1499 (1981). Sabourauds dextrosesub-strat* anvendtes som dyrkningsmedium.
5 *) Totani et al., J.Med.Chem., 24, (12), 1492, (1981).
Forbindelse nr. MIC (flg/ml) 1 0,1 2 3,1 10 3 0,1 4 0,2 8 3,1 12 1,6 15 3,1 15 21 0,1
Forsøg 2
Test for hæmning af pseudohyfedannelse i Candida albicans
Til "Eagle MEN" medium (Nissan 2, Nissui Seiyaku Co., Ltd.) sattes 20 20% bovinserum og Candida albicans KE-2 gærceller podedes i en mængde på 1 x 106 celler/ml (slutinokulumstørrelse), og hver testforbindelse tilsattes ved dobbeltseriefortyndingsmetoden. Efter dyrkning ved 37°C i 18 timer udstrøges hver organisme fra seriefortyndingen, fikseredes på objektglas, farvedes med Giemsas bejse, og forekomst af pseudohyfer 25 iagttoges under mikroskop. Den minimale koncentration, som kunne hæmme dannelsen af pseudohyfer antoges at være den inhibitori ske koncentration for forbindelsen overfor pseudohyfedannelse.
Inhibitorisk koncentration overfor 30 Forbindelse nr. pseudohyfedannelse (jug/ml)_ 1 0,31 2 0,63 5 0,63 7 0,31 35 11 1,25 15 0,63 21 0,16
DK 160826B
ίο
Forsøg 3
Terapeutisk virkning overfor candisosis i mus
Candida albicans KE-2 dyrkedes i Sabourauds dextroseagar ved 28°C i 5 48 timer, og den resulterende kultur suspenderedes i Sabourauds dextro- sesubstrat. De resulterende celler (5 x 105) administreredes intravenøst i halen på Jcl-ICR mus af hunkøn (4 uger gamle,legemsvægt: 18 til 20 g). Hver testforbindelse suspenderet i 2% gummi arabicum administreredes oralt i en dosis på 25 mg/kg to gange dagligt i 5 dage, idet test-10 forbindelsen på den første dag administreres umiddelbart efter infektion og 2 timer senere, mens den på andendagen og de efterfølgende dage administreres 24 timer efter hver af administreringerne den foregående dag.
Til en kontrolgruppe administreredes ingen testforbindelse efter infektionen. 8 mus anvendtes i kontrolgruppen og i hver testgruppe, hvortil 15 testforbindelserne admini stredes. Den terapeutiske virkning vurderedes som overlevelsen på den 15. dag fra infektionen, og resultaterne er vist nedenfor.
Forbindelse nr. Over!evelsesprocent 20 1 87,5 2 100 5 100
Kontrol 0 25
Claims (6)
10 Az er imidazolyl eller triazolyl, R er -C5-al kyl eller phenyl eventuelt substitueret med 1 til 3 substituenter udvalgt blandt halogen, (^-Cg-alkyl og C^Cg-alkoxy, hver af X1 og X2 er hydrogen, halogen, Cj-Cg-alkyl, eller
15 Ci-Cg-alkoxy, Y er C=0 eller C=S, og farmaceutisk acceptable syreadditionssalte deraf.
2. Azolderivater ifølge krav 1 KENDETEGNET ved, at Az er triazolyl, R er C3-C4-alkyl eller phenyl substitueret med 1 eller 2 halo- 20 genatomer, mindst den ene af X1 og X2 er halogen, og Y er C=0 eller C=S.
3. Azol-dioxolan-derivat ifølge krav 1 KENDETEGNET ved, at det er 4-(2,4-dichlorphenyl)-5-(4-fluorphenyl)-2-oxo-4-(IH-1,2,4-triazol-1-ylJmethyl-1,3-di oxolan.
4. Azol-dioxolan-derivat ifølge krav 1 KENDETEGNET ved, at det er 4-(2,4-dichlorphenyl)-5-isopropyl-2-oxo-4-(IH-1,2,4-triazol-l-yl)methyl- 1,3-dioxolan.
5. Azol-dioxolan-derivat ifølge krav 1 KENDETEGNET ved, at det er 4-(4-chlorphenyl)-5-(2,4-dichlorphenyl)-2-ΟΧΟ-4-(1H-1,2,4-triazol-1- 30 yl)methyl-l,3-dioxol an.
6. Farmaceutisk præparat, som kan anvendes til behandling af en patient, som lider af mykotisk infektion, KENDETEGNET ved, at det indeholder en farmakologisk effektiv mængde af et azolderi vat ifølge krav 1 sammen med én eller flere bærere, diluenter og/eller excipienser. 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58133040A JPS6025990A (ja) | 1983-07-20 | 1983-07-20 | トリアゾ−ル系ジオキソラン誘導体 |
| JP13304083 | 1983-07-20 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK354684D0 DK354684D0 (da) | 1984-07-19 |
| DK354684A DK354684A (da) | 1985-01-21 |
| DK160826B true DK160826B (da) | 1991-04-22 |
| DK160826C DK160826C (da) | 1991-10-14 |
Family
ID=15095402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK354684A DK160826C (da) | 1983-07-20 | 1984-07-19 | 4-(imidazolyl eller triazolyl)methyl-1,3-dioxolan eller -thioxo-1,3-dioxolanderivater og antimykotiske praeparater indeholdende disse |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US4612322A (da) |
| EP (1) | EP0133248B1 (da) |
| JP (1) | JPS6025990A (da) |
| KR (1) | KR910009200B1 (da) |
| CA (1) | CA1244039A (da) |
| DE (1) | DE3485281D1 (da) |
| DK (1) | DK160826C (da) |
| ES (1) | ES8602773A1 (da) |
| GB (1) | GB2144124B (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4788190A (en) * | 1986-12-24 | 1988-11-29 | Schering Corporation | 2,4,4-tri- and 2,2,4,4-tetra substituted-1,3-dioxolane antifungal, antiallergy compounds |
| DE3805376A1 (de) * | 1988-02-20 | 1989-08-31 | Basf Ag | Neue azolylmethyloxirane und diese enthaltende fungizide |
| JPH0349799A (ja) * | 1989-07-18 | 1991-03-04 | Sanyo Electric Co Ltd | 洗濯機 |
| JPH0826012B2 (ja) * | 1991-08-23 | 1996-03-13 | 呉羽化学工業株式会社 | 新規な１，３，２−ジオキサチオランｓ酸化物誘導体、その製造方法及びその用途 |
| DE59310066D1 (de) * | 1992-11-04 | 2000-08-03 | Clariant Gmbh | Verfahren zur Herstellung fluorierter Benzile |
| US5686061A (en) * | 1994-04-11 | 1997-11-11 | The Board Of Regents Of The University Of Texas System | Particulate contrast media derived from non-ionic water soluble contrast agents for CT enhancement of hepatic tumors |
| CA2139079C (en) * | 1994-12-23 | 1996-05-28 | K.S. Keshava Murthy | Commercial process for the manufacture of fluconazole and intermediates useful in the manufacture thereof |
| IT1296926B1 (it) * | 1997-12-05 | 1999-08-03 | Zambon Spa | Procedimento per la preparazione di composti ad attivita' antimicotica |
| KR100458866B1 (ko) * | 1999-05-21 | 2004-12-03 | 한국화학연구원 | 1,3-디옥솔란-2-일리덴 유도체 및 그의 제조 방법 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2095236B (en) * | 1981-03-18 | 1985-03-27 | Ici Plc | Heterocyclylmethyl-substituted dioxolanes and their use as fungicides |
| JPS58128383A (ja) * | 1982-01-26 | 1983-07-30 | Sumitomo Chem Co Ltd | トリアゾ−ル系化合物、その製造法およびこれを有効成分として含有する農園芸用殺菌剤、植物生長調節剤または除草剤 |
| EP0094167A3 (en) * | 1982-05-12 | 1984-07-04 | Fbc Limited | Azolyl fungicide and plant growth regulators and compositions containing them |
| EP0106515B1 (en) * | 1982-09-30 | 1988-12-28 | Pfizer Limited | Triazole anti-fungal agents |
| FI834141A7 (fi) * | 1982-11-16 | 1984-05-17 | Ciba Geigy Ag | Foerfarande foer framstaellning av nya arylfenyleterderivat. |
-
1983
- 1983-07-20 JP JP58133040A patent/JPS6025990A/ja active Granted
-
1984
- 1984-07-19 DE DE8484108548T patent/DE3485281D1/de not_active Expired - Fee Related
- 1984-07-19 EP EP84108548A patent/EP0133248B1/en not_active Expired - Lifetime
- 1984-07-19 KR KR1019840004267A patent/KR910009200B1/ko not_active Expired
- 1984-07-19 DK DK354684A patent/DK160826C/da not_active IP Right Cessation
- 1984-07-20 CA CA000459425A patent/CA1244039A/en not_active Expired
- 1984-07-20 ES ES534484A patent/ES8602773A1/es not_active Expired
- 1984-07-20 GB GB08418575A patent/GB2144124B/en not_active Expired
- 1984-07-20 US US06/632,852 patent/US4612322A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DK160826C (da) | 1991-10-14 |
| GB2144124B (en) | 1987-04-01 |
| DK354684D0 (da) | 1984-07-19 |
| GB2144124A (en) | 1985-02-27 |
| KR910009200B1 (ko) | 1991-11-04 |
| EP0133248A2 (en) | 1985-02-20 |
| CA1244039A (en) | 1988-11-01 |
| EP0133248B1 (en) | 1991-11-21 |
| JPH0417957B2 (da) | 1992-03-26 |
| JPS6025990A (ja) | 1985-02-08 |
| GB8418575D0 (en) | 1984-08-22 |
| DK354684A (da) | 1985-01-21 |
| US4612322A (en) | 1986-09-16 |
| KR850001200A (ko) | 1985-03-16 |
| DE3485281D1 (de) | 1992-01-02 |
| ES534484A0 (es) | 1985-12-01 |
| ES8602773A1 (es) | 1985-12-01 |
| EP0133248A3 (en) | 1987-12-23 |
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